The overall purpose of this proposal is to investigate the control of respiratory smooth and skeletal muscles. Our view is that this regulatory system consists of controlling and controlled elements, organized hierarchically and coupled to other physiological systems. The objectives of this program project grant are to characterize linkages (anatomical, biochemical and function) among components of the respiratory system and between the respiratory and other systems, to delineate the features of the controlled and controlling units, and to study the maturation of these units. We will approach these aims using focused systems, cellular, and molecular approaches in a closely related program consisting of seven projects and three cores. Project 1 combines mathematical analysis with experiments in vertebrate and invertebrates to investigate the responses of the respiratory system to disturbances. It tests the idea that these responses are likely to be the result of coupling between neural network controllers and nonlinear controlled elements. Project 2 examines CNS responses to hypoxia in vivo to elucidate its effects on respiratory and vasomotor activity while Project 3 uses in vitro brain slice preparations to study the neural and synaptic effects of hypoxia. Project 4 assesses the anatomical and functional pathways mediating the responses of the carotid body to hypoxia. Project 5 examines the maturation of airway smooth muscle regulation in animals, and in humans with health and disease. Project 6 assesses surface forces affecting long-term upper airway patency and rheological characteristics of fluids lining the upper airways. Project 7 evaluates the role of muscle afferents in respiratory behavior in humans and in animals, particularly the contribution of phrenic afferents to development of central fatigue of the respiratory muscles. Core facilities are designed to facilitate the increased emphasis in this proposal on cellular and subcellular mechanisms. Besides Core A which serves an administrative and coordinating function, Core B will integrate research which employs immunocyto-chemical and anatomical techniques to study cell structure and histochemistry and Core C will serve as a facility for molecular pharmacology and biochemical methods to examine cell-to-cell communication. Each project in this renewal proposal arises directly or indirectly from ongoing work and each attempts to relate questions of system behavior to studies at the cellular level.